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Metabolomic analysis of the mechanism of action of yerba mate extract on Salmonella Typhimurium

ABSTRACT: Background: Salmonella Typhimurium is a gram-negative enteropathogen that infects millions worldwide; the rapid emergence of antibiotic resistant strains has heightened the urgency of developing effective treatment for this pathogen. Previous studies have demonstrated that the aqueous extract of yerba mate (Ilex paraguariensis) provides effective therapy, in vitro, for the drug-resistant S. Typhimurium DT104. Unfortunately, while some of the chemical constituents that contribute to the extract’s antibacterial activity have been identified, the mechanism of action of the extract is still unknown and of crucial importance to its future potential in combating antibiotic resistant bacteria.
Results: Yerba mate extract altered central carbon metabolism in S. Typhimurium, reduced catalase activity by means other than direct inhibition, and did not change membrane integrity (except at the initial 0 time point, where differences were not resolved) despite a significant increase in the production of a cell wall precursor. Additional significant differences were observed in the global metabolic regulators alpha-ketoglutarate and acetylphosphate, the energy-related molecule NAD+, and in an unexpected match to the antibacterial compound yohimbine.
Conclusions: This work provides the first insight into the mechanism of action of yerba mate extract on S. Typhimurium by revealing a major impact on central carbon metabolism, catalase activity, and possible metabolic links to interference in energy production and membrane integrity. The putative identification of the antibacterial compound yohimbine and the many unidentified compounds provides additional avenues for future investigations of novel yerba mate compounds capable of traversing or binding to S. Typhimurium’s membrane.

INSTRUMENT(S): Exactive Plus (Thermo Scientific)

SUBMITTER: Caroline Rempe

PROVIDER: MTBLS359 | MetaboLights | 2017-02-16

REPOSITORIES: MetaboLights

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Project description:The discovery of antibiotics has led to the effective treatment of bacterial infections that were otherwise fatal and has had a transformative effect on modern medicine. Teixobactin is an unusual depsipeptide natural product that was recently discovered from a previously unculturable soil bacterium which is active against several Gram-positive pathogens, including methicillin- resistant Staphylococcus aureus and vancomycin-resistant Enterococci. One of the key attractive features of teixobactin as an antibiotic lead is that resistance could not be generated in a laboratory setting against S. aureus. This is proposed to be a result of the mechanism of action that involves binding to essential bacterial cell wall synthesis building blocks lipid II and lipid III.In the present study, metabolomics was used to investigate the potential metabolic pathways and mode of action involved in mechanisms of antibacterial activity and bacterial killing of the synthetic teixobactin analog Leu10-teixobactin against an MRSA strain, S. aureus ATCC700699. The metabolomes of S. aureus ATCC700699 cells were compared at 1, 3 and 6 h following treatment with Leu10-teixobactin (0.5 µg/ml, i.e. 0.5x MIC) and the untreated controls. Leu10-teixobactin significantly perturbed bacterial membrane lipids (glycerophospholipids and fatty acids), peptidoglycan (lipid I and II) metabolism and cell wall teichoic acid (lipid III) biosynthesis as early as after 1 h of treatment reflecting an initial activity on the cell envelope. Concordant with its time-dependent antibacterial killing action, Leu10-teixobactin caused more perturbations in the levels of key intermediates in pathways of amino-sugar and nucleotide-sugar metabolism and their downstream peptidoglycan and teichoic acid biosynthesis at 3 and 6 h. Significant perturbations in arginine metabolism and interrelated tricarboxylic acid cycle, histidine metabolism, pantothenate and Coenzyme A biosynthesis were also observed at 3 and 6 h.To conclude, this is the first study to provide novel metabolomics mechanistic information which lends to support the development of teixobactin as an antibacterial drug for the treatment of multi-drug resistant Gram-positive infections.

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Metabolomic analysis of the mechanism of action of yerba mate extract on Salmonella Typhimurium

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